Impact of IKZF1 Deletions in the Prognosis of Childhood Acute Lymphoblastic Leukemia in Argentina.

An association of deletions in the IKZF1 gene (IKZF1del) with poor prognosis in acute lymphoblastic leukemia (ALL) has been demonstrated. Additional deletions in other genes (IKZF1plus) define different IKZF1del subsets. We analyzed the influence of IKZF1del and/or IKZF1plus in the survival of children with ALL. From October 2009 to July 2021, 1055 bone marrow samples from patients with ALL were processed by Multiplex ligation-dependent probe amplification (MLPA). Of them, 28 patients died during induction and 4 were lost-in-follow-up, resulting in an eligible 1023 cases. All patients were treated according to ALLIC-BFM-2009-protocol. Patients were classified into three subsets: IKZF1not-deleted (IKZFF1not-del), IKZF1deleted (IKZF1del) and IKZF1del plus deletion of PAX5, CDKN2A, CDKN2B and/or alterations in CRLF2 with ERG-not-deleted (IKZF1plus). The LFSp and SE were calculated with the Kaplan−Meier calculation and compared with a log-rank test. From the 1023 eligible patients, 835 (81.6%) were defined as IKZF1not-del, 94 (9.2%) as IKZF1del and 94 (9.2%) as IKZF1plus. Of them, 100 (9.8%) corresponded to Standard-Risk (SRG), 629 (61.5%) to Intermediate-Risk (IRG) and 294 (28.7%) to High-Risk (HRG) groups. LFSp(SE) was 7 5(2)% for IKZF1not-del, 51 (6)% for IKZF1del and 48 (6)% for IKZF1plus (p-value < 0.00001). LFSp(SE) according to the risk groups was: in SRG, 91 (4)% for IKZF1not-del, 50 (35)% IKZF1del and 100% IKZF1plus (p-value = ns); in IRG, 77 (2)% IKZF1not-del, 61 (10)% IKZF1del and 54 (7)% IKZF1plus (p-value = 0.0005) and in HRG, 61 (4)% IKZF1not-del, 38 (8)% IKZF1del and 35 (9)% IKZF1plus (p-value = 0.0102). The IKZF1 status defines a population of patients with a poor outcome, mainly in IRG. No differences were observed between IKZF1del versus IKZF1plus. MLPA studies should be incorporated into the risk-group stratification of pediatric ALL.

Clonal Myeloproliferative Disorders in Patients with Down Syndrome-Treatment and Outcome Results from an Institution in Argentina.

Children with Down syndrome (DS) are at an increased risk of developing clonal myeloproliferative disorders. The balance between treatment intensity and treatment-related toxicity has not yet been defined. We analyzed this population to identify risk factors and optimal treatment. This single-center retrospective study included 78 DS patients <16 years-old with Transient Abnormal Myelopoiesis (TAM, n = 25), Acute Myeloblastic Leukemia (DS-AML, n = 41) of which 35 had classical Myeloid Leukemia associated with DS (ML-DS) with megakaryoblastic immunophenotype (AMKL) and 6 sporadic DS-AML (non-AMKL). Patients with DS-AML were treated according to four BFM-based protocols. Classical ML-DS vs. non-DS-AMKL were compared and the outcome of ML-DS was analyzed according to treatment intensity. Only four patients with TAM required cytoreduction with a 5-year Event-Free Survival probability (EFSp) of 74.4 (±9.1)%. DS-AML treatment-related deaths were due to infections, with a 5-year EFSp of 60.6 (±8.2)%. Megakaryoblastic immunophenotype was the strongest good-prognostic factor in univariate and multivariate analysis (p = 0.000). When compared ML-DS with non-DS-AMKL, a better outcome was associated with a lower relapse rate (p = 0.0002). Analysis of administered treatment was done on 32/33 ML-DS patients who achieved CR according to receiving or not high-dose ARA-C block (HDARA-C), and no difference in 5-year EFSp was observed (p = 0.172). TAM rarely required treatment and when severe manifestations occurred, early intervention was effective. DS-AML good outcome was associated with AMKL with a low relapse-rate. Even if treatment-related mortality is still high, our data do not support the omission of HDARA-C in ML-DS since we observed a trend to detect a higher relapse rate in the arm without HDARA-C.

Graft reduction surgery is associated with poorer outcome after lung transplantation: a single-centre propensity score-matched analysis.

OBJECTIVES: Implanted lung volume-reduction surgery due to donor/recipient size mismatch could affect both lung function and survival. We examined the outcomes of lung volume-reduction procedures post-lung transplant. METHODS: We retrospectively reviewed 366 consecutive adult lung transplants carried out between January 2014 and December 2018 at one single centre. Patients were divided into either a non-reduced-size lung transplant or a reduced-size lung transplant (RT) group. To adjust for covariates, a propensity score analysis was performed. Survival was estimated using the Kaplan-Meier method. Differences were considered significant with P-values <0.05. RESULTS: In the RT group, 45 patients (12.3%) had some type of graft reduction surgery: 31 (68.9%) patients had pulmonary lobectomies and 14 (31.1%) wedge resections. Of the total cohort, 30 patients (8.2%) were prioritized, 23% of whom required graft reduction surgery. The propensity score analysis matched 41 patients in each group. In the RT group, there was an increased need for cardiopulmonary bypass (P = 0.017) during surgery and extracorporeal membrane oxygenation (P = 0.025) after lung transplant. Furthermore, the median length of mechanical ventilation was higher (P = 0.008), and lung function at discharge, 3 and 6 months post-lung transplant was significantly lower in the RT group (P < 0.05). Survival analysis demonstrated a significantly poorer overall outcome at 1, 3 and 5 years post-lung transplantation in patients with a reduced graft (P = 0.007), while the 1-year conditional survival was also worse in this group (P = 0.025). CONCLUSIONS: Graft reduction surgery in lung transplant recipients is associated with lower pulmonary function and poorer overall survival. However, it does allow transplantation in prioritized recipients for whom it might otherwise be impossible to find an organ of suitable size.

New opacities in lung allograft after transbronchial cryobiopsy.

BACKGROUND: The occurrence of radiological opacities post-transbronchial cryobiopsy may pose serious difficulties in differential diagnosis and management of lung allografts. This prospective study evaluated the frequency, characteristics, and evolution of new lung opacities after performing transbronchial cryobiopsy. METHODS: From February 2018 to June 2018, 22 of 51 consecutive patients with an indication for transbronchial cryobiopsy underwent computed tomography (CT) of the thorax before and at 1, 4, and 8 weeks post-cryobiopsy. New CT images, required by the transplant team, were also evaluated during the next 6 months. Histological findings of transbronchial cryobiopsy and microbiological studies on bronchoalveolar lavage were evaluated as risk factors for opacities. RESULTS: After obtaining 112 cryobiopsy samples, 46 opacities >10 mm, including ground-glass, solid, cavitated, or a combination of these lesions were observed in 20 (91%) patients on post-cryobiopsy CT. All ground-glasses opacities on CT disappeared at 4 weeks. A single cavitated opacity persisted at 6 months. The remaining opacities disappeared or were decreased to <10 mm by 8 weeks. No correlations of the number, type, or evolution of opacities with the number or volume of cryobiopsy samples obtained, or with the histological diagnosis, type of transplant, or microbiologic culture results were observed. CONCLUSION: New pulmonary opacities >10 mm occur frequently after transbronchial cryobiopsy; a few may persist beyond 6 months. CT studies are recommended before implementing transbronchial cryobiopsy, whenever possible.

No benefit of Interfant protocols compared to BFM-based protocols for infants with acute lymphoblastic leukemia. Results from an institution in Argentina.

BACKGROUND: Infant acute lymphoblastic leukemia (ALL) is an infrequent disease characterized by clinical and biological features related to poor prognosis. Adapted therapies were designed without a clear consensus regarding the best treatment options. We aimed to compare the outcome between infant ALL cases receiving Interfant versus BFM-based protocols. PROCEDURE: This is a retrospective observational study. From April 1990 to June 2018, infant ALL cases were enrolled in one of the five consecutive treatment protocols. Clinical, demographic, and biological features and outcome were evaluated. A comparative analysis was performed between Interfant protocols and BFM-based protocols. RESULTS: During the studied period, 1913 ALL patients were admitted and 116 (6%) were infants. Treatment administered was: ALL-BFM'90 (n = 16), 1-ALL96-BFM/HPG (n = 7), Interfant-99 (n = 39), Interfant-06 (n = 35), and ALLIC-BFM'2009 (n = 19). The 5-year event-free survival probability (EFSp) was 31.9(standard error [SE] 4.6)% for the entire population, with a significant difference among risk groups according to Interfant-06 criteria (P = .0029). KMT2A-rearrangement status was the strongest prognostic factor (P = .048), independently of the protocol strategy. The median time for relapse was 24.1 months for patients with minimal residual disease (MRD)-negative versus 11.5 months for those with MRD-positive (P = .0386). EFSp and cumulative relapse risk probability (CRRp) were similar. Interfant protocols showed comparable induction (8.1% vs 7.1%, P = .852) and complete remission mortality (21.6% vs 28.6%, P = .438), failing to reduce the relapse rate (48.5% vs 30.7%, P = .149). CONCLUSIONS: Interfant protocols and BFM-based protocols presented comparable results. The risk group stratification proposed by Interfant-06 was validated by our results, and MRD seems useful to identify patients with an increased risk of early relapse.

Intravenous immunoglobulin to prevent myasthenic crisis after thymectomy and other procedures can be omitted in patients with well-controlled myasthenia gravis.

BACKGROUND: Myasthenic crisis (MC) is a potentially life-threatening complication of myasthenia gravis. Its precipitating factors include surgical procedures, particularly thymectomy. The role of preoperative intravenous immunoglobulin (IVIg) in preventing MC in patients scheduled for thymectomy and other surgery with general anaesthesia is unknown. Our objective was to test the hypothesis that preoperative IVIg is effective in preventing myasthenic crisis in patients with myasthenia gravis scheduled for surgery under general anaesthesia, including thymectomy. METHODS: A prospective, randomized, double-blind, single-centre study was conducted over a 4-year period. The treatment group received IVIg, 0.4 g/kg/day preoperatively for 5 consecutive days, and the placebo group received saline solution under the same conditions. The two groups were age-matched, with similar functional status, and Myasthenia Gravis Foundation of America class. All patients had well-controlled myasthenia gravis with minimal manifestations before surgery. The primary outcome measured was MC. Intubation times, time in the recovery room, number of postoperative complications, and days of hospitalization were the secondary outcomes measured. RESULTS: A total of 47 patients were randomized, 25 to the IVIg group and 22 to placebo. There were 19 men and 28 women, with a mean age of 58.6 years, mean body mass index of 27.8 kg/m2, and mean acetylcholine receptor antibodies of 12.9 nmol/l. The mean forced vital capacity was 84.4%. The mean quantitative myasthenia gravis sum score was 6.3. Ten patients (five in each arm) had a history of MC. Thymectomy was performed in 16 patients. Only one patient in the placebo group presented with MC requiring non-invasive ventilation (but no reintubation) for 6 days. Neither differences between groups in the univariate analysis nor risk factors for MC in the multivariate analysis were found. CONCLUSIONS: Preoperative IVIg to prevent MC does not appear to be justified in well-controlled myasthenia gravis patients. This study provides class I evidence that preparation with IVIg to prevent MC is not necessary in well-controlled myasthenia gravis patients scheduled for surgery with general anaesthesia.

Lung transplantation in two cystic fibrosis patients infected with previously pandrug-resistant Burkholderia cepacia complex treated with ceftazidime-avibactam.

We describe two cystic fibrosis patients infected with pandrug-resistant Burkholderia cepacia complex, with the exception of ceftazidime-avibactam, who received prophylaxis with this antibiotic during lung transplantation. Although both patients had a post-operative relapse of respiratory infection, one with positive blood cultures, ceftazidime-avibactam treatment yielded a favourable outcome. 12 months after transplantation, one patient presented an excellent clinical outcome. However, the other patient died 10 months later due to severe B. cepacia sinusitis with intracranial invasion.

Lung Transplantation in Cystic Fibrosis and the Impact of Extracorporeal Circulation. / El trasplante pulmonar en la fibrosis quística y la influencia de la circulación extracorpórea.

INTRODUCTION: Lung disease is the major cause of death among cystic fibrosis (CF) patients, affecting 80% of the population. The impact of extracorporeal circulation (ECC) during transplantation has not been fully clarified. This study aimed to evaluate the outcomes of lung transplantation for CF in a single center, and to assess the impact of ECC on survival. METHODS: We performed a retrospective observational study of all trasplanted CF patients in a single center between 1992 and 2011. During this period, 64 lung transplantations for CF were performed. RESULTS: Five- and 10-year survival of trasplanted patients was 56.7% and 41.3%, respectively. Pre-transplantation supplemental oxygen requirements and non-invasive mechanical ventilation (NIMV) do not seem to affect survival (P=.44 and P=.63, respectively). Five- and 10-year survival among patients who did not undergo ECC during transplantation was 75.69% and 49.06%, respectively, while in those did undergo ECC during the procedure, 5- and 10-year survival was 34.14% and 29.87%, respectively (P=.001). PaCO2 is an independent risk factor for the need for ECC. CONCLUSIONS: The survival rates of CF patients undergoing lung transplantation in our hospital are similar to those described in international registries. Survival is lower among patients receiving ECC during the procedure. PaCO2 is a risk factor for the need for ECC during lung transplantation.

Influence of early neurological complications on clinical outcome following lung transplant.

BACKGROUND: Neurological complications after lung transplantation are common. The full spectrum of neurological complications and their impact on clinical outcomes has not been extensively studied. METHODS: We investigated the neurological incidence of complications, categorized according to whether they affected the central, peripheral or autonomic nervous systems, in a series of 109 patients undergoing lung transplantation at our center between January 1 2013 and December 31 2014. RESULTS: Fifty-one patients (46.8%) presented at least one neurological complication. Critical illness polyneuropathy-myopathy (31 cases) and phrenic nerve injury (26 cases) were the two most prevalent complications. These two neuromuscular complications lengthened hospital stays by a median period of 35.5 and 32.5 days respectively. However, neurological complications did not affect patients' survival. CONCLUSIONS: The real incidence of neurological complications among lung transplant recipients is probably underestimated. They usually appear in the first two months after surgery. Despite not affecting mortality, they do affect the mean length of hospital stay, and especially the time spent in the Intensive Care Unit. We found no risk factor for neurological complications except for long operating times, ischemic time and need for transfusion. It is necessary to develop programs for the prevention and early recognition of these complications, and the prevention of their precipitant and risk factors.

Intrapleural Fibrinolysis with Urokinase Versus Alteplase in Complicated Parapneumonic Pleural Effusions and Empyemas: A Prospective Randomized Study.

BACKGROUND: Pleurofibrinolysis has been reported to be potentially beneficial in the management of complicated parapneumonic effusions (CPPE) and empyemas in the adult population. METHODS: Prospective, controlled, randomized, and double-blind study, to evaluate intrapleural alteplase 10 mg (initially 20 mg was considered but bleeding events forced dose reduction) versus 100,000 UI urokinase every 24 h for a maximum of 6 days in patients with CPPE or empyemas. The primary aim was to evaluate the success rate of each fibrinolytic agent at 3 and 6 days. Success of therapy was defined as the presence of both clinical and radiological improvement, making additional fibrinolytic doses unnecessary, and eventually leading to resolution. Secondary outcomes included the safety profile of intrapleural fibrinolytics, referral for surgery, length of hospital stay, and mortality. RESULTS: A total of 99 patients were included, of whom 51 received alteplase and 48 urokinase. Success rates for urokinase and alteplase at 3 and 6 days were not significantly different, but when only the subgroup of CPPE was considered, urokinase resulted in a high proportion of cures. There were no differences in mortality or surgical need (overall, 3 %). Five (28 %) patients receiving 20 mg of alteplase and 4 (12 %) receiving 10 mg presented serious bleeding events. CONCLUSIONS: If intrapleural fibrinolytics are intended to be used, urokinase may be more effective than alteplase in patients with non-purulent CPPE and have a lower rate of adverse events.

Early and mid-term results of lung transplantation with donors 60 years and older.

OBJECTIVES: There are doubts about the age limit for lung donors and the ideal donor has traditionally been considered to be one younger than 55 years. The objective of this study was to compare the outcomes in lung transplantation between organs from donors older and younger than 60 years. METHODS: We performed a retrospective observational study comparing the group of patients receiving organs from donors 60 years or older (Group A) or younger than 60 years (Group B) between January 2007 and December 2011. Postoperative evolution and mortality rates, short-term and mid-term postoperative complications, and global survival rate were evaluated. RESULTS: We analysed a total of 230 lung transplants, of which 53 (23%) involved lungs from donors 60 years of age or older (Group A), and 177 (77%) were from donors younger than 60 years (Group B). Three (5.7%) patients from Group A and 14 patients (7.9%) from Group B died within 30 days (P = 0.58). The percentage of patients free from chronic lung allograft dysfunction at 1-3 years was 95.5, 74.3 and 69.3% for Group A, and 94.5, 84.8 and 73.3% for Group B, respectively (P = 0.47). There were no statistically significant differences between Groups A and B in terms of survival at 3 years, (69.4 vs 68.8%; P = 0.28). CONCLUSIONS: Our results support the idea that lungs from donors aged 60-70 years can be used safely for lung transplantation with comparable results to lungs from younger donors in terms of postoperative mortality and mid-term survival.